AbstractThe MET oncogene encodes an unconventional receptor tyrosine kinase with pleiotropic functions: it causes and sustains neoplastic transformation when genetically altered (‘oncogene addiction’), and fosters cancer cell survival and tumour dissemination when transcriptionally activated in the context of an adaptive response to adverse microenvironmental conditions (‘oncogene expedience’). Moreover, MET is an intrinsic modulator of self-renewal and clonogenic ability of cancer stem cells (‘oncogene inherence’). The seminar will provide fresh knowledge on MET function in cancer by focusing on newly identified genetic abnormalities in tumour cells and recently described non-mutational MET activities in stromal and cancer stem cells. It will be discussed how MET drives cancer clonal evolution and progression towards metastasis, both ab initio and under therapeutic pressure. Intriguingly, MET, a master gene controlling invasive growth, is a driver gene in a relatively high number of ‘Cancers of Unknown Primary’, a prototype of the metastatic disease. The use of MET inhibitors in the clinic, with a critical appraisal of failures and successes will be elaborated. Ultimately, it will be advocate a rationale to improve the outcome of anti-MET therapies based on thorough consideration of the entire spectrum of MET-mediated biological responses, which implicates adequate patient stratification, meaningful biomarkers and appropriate clinical endpoints